Acid-catalyzed addition of water to an alkene and an alkyne
In an acid-catalyzed addition of water to an alkene, the product will be a markovnikov addition where water is added to the more stable carbocation to form an alcohol. The water is protonated by the sulfuric acid (or any suitable acid) and is then deprotonated by the alkene. This forms a carbocation in the more stable position. In the case above, the middle carbon is becomes a 2° carbocation, where as a terminal carbon would form a 1° carbocation (unstable). The water attacks the carbocation and is then deprotonated by the surrounding water, forming the alcohol. The reaction takes place in water, which is why water can just come in and protonate and deprotonate.
The acid-catalyzed addition of water to an alkyne is not as simple. As before, the water is protonated by the sulfuric acid and is attacked by the alkyne. However here, the alkyne and water form a sort of “pi-complex” at the hydrogen. Here, there is partial positive charges forming at both ends of the triple bond. Another water molecule comes and attacks the alkyne at the internal carbon, because here the partial positive charge from the pi-complex is more stable due to being a 2° carbon (where as the terminal carbon is a 1° carbon). This second water molecule breaks the pi-complex and forms a protonated enol, an alkene with a double bond. The water then deprotonates the enol and it then is tautomerized from an enol to a ketone. The electrons on the hyrdoxyl group flow down and form a protonated carbonyl (a carbon-oxygen double bond). This is then deprotonated by water to form the stable product, a ketone. The idea behind keto-enol tautomerism is that there is a rapid equilibrium between the enol and keto form of the compound, however there is more of the keto form due to it being the more stable.
Time for some scienceeeeeee! (ﾉ◕ヮ◕)ﾉ*:･ﾟ✧
Although a lot of chemistry can be reasoned through, there are some things that have to be learned by brute memorization; benzene derivative nomenclature is one of these things. All of these compounds have systematic names, but the common names tend to be more widely (if not exclusively) used. (and let’s face it, the name ‘anisole’ is just cooler than ‘methoxybenzene’, you know?)
Toluene (“methylbenzene”) is a liquid widely used as a nonpolar solvent. As toluene is thought to be noncarcinogenic, it has largely replaced benzene as a solvent.
Styrene (“vinyl benzene”) is a sweet-smelling liquid that is the precursor to polystyrene plastics. Styrene is produced industrially by the catalytic dehydrogenation of ethylbenzene.
Cumene (“isopropylbenzene”) is a liquid that is an intermediate in the synthesis of acetone and phenol from benzene and propylene (the cumene process). It is also occasionally used as a solvent.
Phenol (“hydroxybenzene”; formerly “carbolic acid”) is a transparent solid. Dilute solutions of phenol have antiseptic and analgesic properties, but concentrated solutions are corrosive and toxic.
Aniline (“phenylamine”, “aminobenzene”) is a fishy-smelling liquid. Aniline was originally isolated from the dye indigo, and can be used as a precursor for many dyes and pigments.
Anisole (“methoxybenzene”) is a liquid that smells faintly of anise. Anisole is used in the perfume industry as a starting material to synthesize many different fragrances.
Benzaldehyde (“benzenecarbaldehyde”) is a liquid that was first isolated from bitter almonds. Not surprisingly, benzaldehyde has a strong scent of almonds and can be used as a flavoring agent.
Benzoic acid is a solid that was first isolated from gum benzoin, a tree resin. Benzoic acid and its salts are often used as preservatives in acidic foods like fruit juice and carbonated drinks.
Benzamide is a solid, and is the amide of benzoic acid. Its primary use is as a precursor to other compounds, and is widely used in the pharmaceutical industry for this purpose.
Acetophenone (“phenyl methyl ketone”) is a pleasant-smelling liquid found naturally in many foods, such as bananas and apricots. It is often used in fragrances for this reason.
Benzonitrile (“cyanobenzene”) is a liquid that has a faint almond smell. It was first discovered as a decomposition product of ammonium benzoate and used as both a solvent and a reagent.
Benzenesulfonic acid is a solid produced by the sulfonation of benzene. Although it was formerly used to synthesize phenol, this purpose has been replaced by the cumene process.
Carbazoles are heterocyclic compounds that feature indole with a fused benzene ring. They are reactive at the 1 (or 8), 3 (or 6), and 9 positions of the molecule, where substituents are usually electrophiles (E+) due to the nucleophilic nature of carbazoles.
There exist many reviews of improved approaches to synthesizing carbazoles, but here I’ll talk about the classic ones for the sake of mentioning them; these include the Borsche-Drechsel cyclization, Bucherer carbazole synthesis, and Graebe-Ullmann reaction.
In the Borsche-Drechsel cyclization, phenylhydrazine and a ketone condense under acidic conditions to form an imine, after which further reaction with acid leads to the cyclization; subsequent oxidation gives carbazole.
The mechanism of the cyclization step is something worth describing in detail. Under acidic conditions (e.g. HCl), an iminium ion forms, followed by deprotonation to generate a structure set up for a [3,3] rearrangement. The resulting di-ketimine is protonated under equilibrating conditions; deprotonation by a chloride atom and ring-closing result in the tetrahydrocarbazole. The last step - an oxidation reaction - leads to carbazole (this can be carried out by Red Lead, according to Wikipedia…).
I won’t talk about the Bucherer carbazole synthesis here because there is an immense amount of literature out there about this reaction’s utility in carbazole synthesis. The mechanism is something to explore further.
Another synthetic method is the Graebe-Ullmann synthesis, where N-phenyl-1,2-diaminobenzene reacts with nitrous acid to form a 1,2,3-triazole, which is unstable and undergoes thermal decomposition to the carbazole.
The first few steps of the mechanism illustrate the reaction between nitrous acid and water in the formation of the species circled in red. This species then reacts with the di-amine to nitrosylate the more nucleophilic amine. Protonation of the N=O oxygen activates the nitrosamine for nucleophilic attack by the other amine. Proton transfer and subsequent deprotonation and elimination of water gives the triazole.
How the triazole decomposes to carbazole is not mechanistically well-known, so the arrows I’m showing are what makes sense to me. Assuming that the reaction with nitrous acid and heating are done in one-pot, expulsion of N2 gas is followed by simultaneous deprotonation and protonation to yield carbazole, nitrite, and hydronium ion (nitrite and the hydronium ion can react with each other to form nitrous acid and water).
In terms of more recent advancements on the synthesis of carbazoles, many of them can be found here, which entail metal-catalyzed methods. So, why this talk about carbazoles? Well, two recent total synthesis papers feature this nitrogen heterocycle as an important scaffold in accomplishing the total synthesis of carbazole-containing natural products - Garg’s synthesis of Tubingensin A and Baran’s synthesis of Dixiamycin B:
I highly recommend reading these papers. Garg’s paper builds upon utilizing much of his group’s work on benzynes and arynes as synthetically useful compounds in making complex natural products, while Baran’s paper features the accomplishment of a key oxidative dimerization step in the synthesis of dixiamycin B, which his group carried out through an electrochemical approach. References for the curious:
1. Garg et al. J. Am. Chem. Soc., 2014, 136 (8), pp 3036–3039.
2. Baran et al. J. Am. Chem. Soc., 2014, 136 (15), pp 5571–5574.